Interactions of intrinsically disordered proteins with the unconventional chaperone human serum albumin: From mechanisms of amyloid inhibition to therapeutic opportunities

Human Serum Albumin (HSA), the most abundant protein in plasma, serves a diverse repertoire of biological functions including regulation of oncotic pressure and redox potential, transport of serum solutes, but also chaperoning of misfolded proteins. Here we review how HSA interacts with a wide spectrum of client proteins including intrinsically disordered proteins (IDPs) such as A beta, the islet amyloid peptide (IAPP), alpha synuclein and stressed globular proteins such as insulin. The comparative analysis of the HSA chaperone - client interactions reveals that the amyloid-inhibitory function of HSA arises from at least four emerging mechanisms. Two mechanisms (the monomer stabilizer model and the monomer competitor model) involve the direct binding of HSA to either IDP monomers or oligomers, while other mechanisms (metal chelation and membrane protection) rely on the indirect modulation by HSA of other factors that drive IDP aggregation. While HSA is not the only extracellular chaperone, given its abundance, HSA is likely to account for a significant fraction of the chaperoning effects in plasma, thus opening new therapeutic opportunities in the context of the peripheral sink hypothesis.